The present invention relates to aminobenzoic acid derivatives that exhibit anti-tumorigenic activity, and more particularly to haloacetylated, aminobenzoic acid derivatives that exhibit anti-tumorigenic activity.
Cancer is a disease that afflicts many in the general population. As a result, a variety of therapies have been developed for treating these malignancies, such as radiation, chemotherapeutics, antisense oligonucleotides, monoclonal antibodies and vaccines. However, even with these therapeutic options, cancer still remains a serious life threatening disease.
In addition to radiation and surgery, chemotherapy is a standard treatment option for those diagnosed with a malignancy. Numerous compounds have been tested and approved for use. However, most chemotherapeutics while being toxic to malignant cells are unfortunately toxic to normal cells. As a result, the side effects of chemotherapeutics are often severe. Recipients of chemotherapeutics often develop complications such as immune suppression which often lead to a variety of opportunistic infections. In many circumstances, patients do not succumb to the cancer, but to the side effects of the chemotherapy.
The development of promising chemotherapeutics is also hampered by the unavailability of large quantities of the potential agent for clinical trials. The vast majority of chemotherapeutics have complex multi-cyclic structures that renders synthesis difficult at best. Thus, natural sources of the potential agent, which are often limited, can become a limiting factor in widespread assessment of anti-neoplastic efficacy of the potential agent.
Accordingly, there is a continuing need in the art for new chemotherapeutics for the treatment of cancer, and especially chemotherapeutics that can be readily synthesized by conventional organic techniques. There is also a need in the art for chemotherapeutics that exhibit preferential toxicity to malignant cells to minimize the unwanted side effects commonly associated with chemotherapeutic agents.
It is, therefore, an object of the present invention to provide new agents for inhibiting tumor cell growth, which can be readily synthesized by conventional organic techniques. It is also an object of the present invention to provide agents that exhibit preferential toxicity to malignant cells.
The present invention provides a class of compounds useful for the inhibition of malignant cell growth (e.g., tumors). In one embodiment, the present invention provides m-haloacetoamido, benzoic acid derivatives having the formula: 
wherein X is a halogen selected from the group consisting of chlorine, bromine and iodine, and independently Y is a substituent selected from the group consisting of urea, ethoxide, xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94R, wherein R is hydrogen, an alkyl or an aryl, and xe2x80x94Nxe2x80x94R1, wherein R1 is an alkyl, a heterocyclic or an amino acid ester, or an acid addition salt thereof. Examples of the m-haloacetoamido, benzoic acid derivatives are 3-chloroacetoamido, benzoylurea, 3-bromoacetoamido, benzoylurea, 3-iodoacetoamido, benzoylurea, ethyl-3-chloroacetoamido, benzoate, ethyl-3-bromoacetoamido, benzoate and ethyl-3-iodoacetoamido, benzoate.
In another embodiment, the present invention provides p-haloacetoamido, benzoic acid derivatives having the formula: 
wherein X is a halogen selected from the group consisting of chlorine, bromine and iodine, and independently Y is a substituent selected from the group consisting of urea, ethoxide, xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94R, wherein R is hydrogen, an alkyl or an aryl, and xe2x80x94Nxe2x80x94R1, wherein R1 is an alkyl, a heterocyclic or an amino acid ester, or an acid addition salt thereof. Examples of the p-haloacetoamido, benzoic acid derivatives are 4-chloroacetoamido, benzoylurea, 4-bromoacetoamido, benzoylurea, 4-iodoacetoamido, benzoylurea, ethyl-4-chloroacetoamido, benzoate, ethyl-4-bromoacetoamido, benzoate and ethyl-4-iodoacetoamido, benzoate.
The present invention also provides intermediate compounds for synthesizing the meta- and para-haloacetoamido, benzoic acid derivatives. In one embodiment, the present invention provides an aminobenzoic acid derivative, having the formula: 
In another embodiment, the present invention provides as aminobenzoic acid derivative, having the formula: 
A method of inhibiting the growth of malignant cells is provided by administering to the cells, an effective amount of the haloacetoamido, benzoic acid derivatives of formula (I) or an acid addition salt thereof. A method of inhibiting the growth of malignant cells is also provided by administering to the cells an effective amount of a haloacetoamido, benzoic acid derivative of formula (II) or an acid addition salt thereof. The present invention also provides a method of inhibiting mitosis in malignant cells by treating the cells with an effective amount of a haloacetoamido, benzoylurea derivatives of formula (I) or an acid addition salt thereof.
The present invention also provides methods of synthesizing the compounds of formula (I), (II), (III) and (IV). In addition to formulations containing effective amounts of the haloacetoamido, benzoic acid derivatives of formula (I), (II), or their acid addition salts, in a physiologically acceptable carrier, are provided.
Advantageously, the compounds of the present invention are effective in inhibiting malignant cell growth, while exhibiting significantly reduced cytotoxicity to normal cells. The compounds of the present invention also provide the advantage of a simple cyclic structure which can be readily synthesized by those skilled in the art. These and other advantages of the present invention are further described below.